Repetitive use of levosimendan for treatment of chronic advanced heart failure: Clinical evidence, practical considerations, and perspectives: An expert panel consensus (original) (raw)
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International journal of cardiology, 2017
Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach. In these settings, levosimendan has potential advantages over conventional inotropes (catecholamines and phosphodiesterase inhibitors), such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life. However, previous clinical studies of intermittent infusions of levosimendan were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians from 12 European countries met in Rome on November 24-25, 2016 to review the liter...
European Heart Journal Supplements, 2017
Maintaining adequate quality of life (QoL) is an important therapeutic objective for patients with advanced heart failure and, for some patients, may take precedence over prolonging life. Achieving good QoL in this context may involve aspects of patient care that lie outside the familiar limits of heart failure treatment. The inodilator levosimendan may be advantageous in this setting, not least because of its sustained duration of action, ascribed to a long-acting metabolite designated OR-1896. The possibility of using this drug in an outpatient setting is a notable practical advantage that avoids the need for patients to attend a clinic appointment. Intermittent therapy can be integrated into a wider system of outreach and patient monitoring. Practical considerations in the use of levosimendan as part of a palliative or end-of-life regimen focused on preserving QoL include the importance of starting therapy at low doses and avoiding bolus administration unless immediate effects are required and patients have adequate baseline arterial blood pressure.
Intermittent levosimendan treatment in patients with severe congestive heart failure
Clinical Research in Cardiology, 2013
Objective Levosimendan (LS) is a novel inodilator for the treatment of severe congestive heart failure (CHF). In this study, we investigated the potential long-term effects of intermittent LS treatment on the pathophysiology of heart failure. Methods Thirteen patients with modest to severe CHF received three 24-h intravenous infusions of LS at 3-week intervals. Exercise capacity was determined by bicycle ergospirometry, well-being assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ) and laboratory parameters of interest measured before and after each treatment. Results One patient experienced non-sustained periods of ventricular tachycardia (VT) during the first infusion and had to discontinue the study. Otherwise the LS infusions were well tolerated. Exercise capacity (VO 2max) did not improve significantly during the study although symptoms decreased (P \ 0.0001). Levels of plasma NT-proANP, NT-proBNP and NT-proXNP decreased 30-50 % during each infusion (P \ 0.001 for all), but the changes disappeared within 3 weeks. Although norepinephrine (NE) appeared to increase during the first treatment (P = 0.019), no long-term changes were observed. Conclusion Intermittent LS treatments decreased effectively and repetitively plasma vasoactive peptide levels, but no carryover effects were observed. Patients' symptoms decreased for the whole study period although there was no objective improvement of their exercise capacity. The prognostic significance of these effects needs to be further studied.
The inodilator levosimendan in repetitive doses in the treatment of advanced heart failure
European Heart Journal Supplements, 2017
Inotropes may be an appropriate response for some patients with advanced heart failure who remain highly symptomatic despite optimization of evidence-based therapy. These patients need to be supported waiting for a heart transplant or ventricular assist device, or may be candidates for inotropy as an intervention in its own right to maintain a patient in the best achievable circumstances. Objectives in such a situation include relieving symptoms, improving quality of life and reducing unplanned hospitalizations and the costs associated with such admissions. Levosimendan, a calcium sensitizer and potassium channel opener with inotrope and vasodilator actions, has emerged as a potentially valuable addition to the armamentarium in this context, used in repeated or intermittent cycles of therapy. Detailed proposals and guidance are offered for the identification of candidate patients with good prospects of a beneficial response to levosimendan, and for the safe and effective implementation of a course of therapy.
Medical Science Monitor, 2014
Departmental sources Background: Levosimendan (LS) is a novel inodilator that improves cardiac performance, central hemodynamics, and symptoms of patients with decompensated chronic heart failure. The aim of this study was to compare the effects of single and repeated LS infusion on left ventricular performance, biomarkers, and neurohormonal activation in patients with acute heart failure. Material/Methods: Twenty-nine consecutive patients with acute exacerbation of advanced heart failure were included in this study. LS was initiated as a bolus of 6 μg/kg followed by a continuous infusion of 0.1 μg/kg/min for 24 hours in both groups who received intravenous single and repeated (baseline and at 1 and 3 months) treatment. Physical examination, echocardiography, and biochemical tests (brain natriuretic peptide, tumour necrosis factor-a, interleukin-1b, 2, and 6) were performed before treatment and on 3 day of the treatment. The last evaluation was performed at 6 month after the baseline treatment. Results: Twenty male and 9 female patients with mean age of 60.2±7.4 years were included in this study. A significant improvement in New York Heart Association functional status and myocardial performance index was detected only in the repeated LS treated patients at 6 month compared to the pretreatment status (p=0.03 and p<0.001; respectively). In addition, a significant decrease in brain natriuretic peptide (p<0.01) and plasma interleukin-6 (p=0.05) levels were also achieved only in patients who were given repeated LS. Conclusions: Our study showed that repeated LS treatment is more effective compared to the single dose LS treatment in improving clinical status, hemodynamic and laboratory parameters in patients with acute exacerbation of advanced heart failure.
ESC Heart Failure
Hospitalization for acute heart failure (HF) is associated with a substantial morbidity burden and with associated healthcare costs and an increased mortality risk. However, few if any major medical innovations have been witnessed in this area in recent times. Levosimendan is a first-in-class calcium sensitizer and potassium channel opener indicated for the management of acute HF. Experience in several clinical studies has indicated that administration of intravenous levosimendan in intermittent cycles may reduce hospitalization and mortality rates in patients with advanced HF; however, none of those trials were designed or powered to give conclusive insights into that possibility. This paper describes the rationale and protocol of LeoDOR (levosimendan infusions for patients with advanced chronic heart failure), a randomized, double-blind, placebo-controlled, international, multicentre trial that will explore the efficacy and safety of intermittent levosimendan therapy, in addition to optimized standard therapy, in patients following hospitalization for acute HF. Salient features of LeoDOR include the use of two treatment regimens, in order to evaluate the effects of different schedules and doses of levosimendan during a 12 week treatment phase, and the use of a global rank primary endpoint, in which all patients are ranked across three hierarchical groups ranging from time to death or urgent heart transplantation or implantation of a ventricular assist device to time to rehospitalization and, lastly, time-averaged proportional change in N-terminal pro-brain natriuretic peptide. Secondary endpoints include changes in HF symptoms and functional status at 14 weeks.
Intermittent levosimendan infusions in advanced heart failure: a real world experience
Journal of International Medical Research, 2017
Objective: To analyse the effects of levosimendan infusions in advanced heart failure. Methods: Patients with advanced heart failure treated with repeated levosimendan infusions were retrospectively compared with controls. Clinical, blood and echocardiographic parameters were obtained at baseline and after 12 months, and before and after each levosimendan infusion. Hospitalizations for heart failure and in-hospital length of stay in the 6 months before enrolment and after 6 and 12 months were recorded, along with 1-year mortality. Results: Twenty-five patients treated with levosimendan and 25 controls were studied. After each levosimendan infusion, ventricular function and various clinical and metabolic parameters were improved. After 12 months, left ventricular ejection fraction (LVEF) had improved compared with baseline in the levosimendan group. The 1-year mortality rate was similar in both groups. During the 6 months before enrolment, hospitalizations were fewer in controls compared with the levosimendan group; after 6 and 12 months they increased in controls and decreased in the levosimendan group. Seven patients were super-responders to levosimendan, with LVEF improving more than 20% and hospitalizations being reduced at 12 months compared with the rest of the levosimendan group. Conclusion: Intermittent levosimendan improved LVEF and decreased hospitalizations in advanced heart failure and represents a therapeutic option for patients whose disease is worsening.
Intermittent Levosimendan Infusions in Advanced Heart Failure
Journal of Cardiovascular Pharmacology, 2012
Objective: To analyse the effects of levosimendan infusions in advanced heart failure. Methods: Patients with advanced heart failure treated with repeated levosimendan infusions were retrospectively compared with controls. Clinical, blood and echocardiographic parameters were obtained at baseline and after 12 months, and before and after each levosimendan infusion. Hospitalizations for heart failure and in-hospital length of stay in the 6 months before enrolment and after 6 and 12 months were recorded, along with 1-year mortality. Results: Twenty-five patients treated with levosimendan and 25 controls were studied. After each levosimendan infusion, ventricular function and various clinical and metabolic parameters were improved. After 12 months, left ventricular ejection fraction (LVEF) had improved compared with baseline in the levosimendan group. The 1-year mortality rate was similar in both groups. During the 6 months before enrolment, hospitalizations were fewer in controls compared with the levosimendan group; after 6 and 12 months they increased in controls and decreased in the levosimendan group. Seven patients were super-responders to levosimendan, with LVEF improving more than 20% and hospitalizations being reduced at 12 months compared with the rest of the levosimendan group. Conclusion: Intermittent levosimendan improved LVEF and decreased hospitalizations in advanced heart failure and represents a therapeutic option for patients whose disease is worsening.
European journal of heart failure, 2018
The LION-HEART study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial evaluating the efficacy and safety of intravenous administration of intermittent doses of levosimendan in outpatients with advanced chronic heart failure. Sixty-nine patients from 12 centres were randomly assigned at a 2:1 ratio to levosimendan or placebo groups, receiving treatment by a 6-hour intravenous infusion (0.2 μg/kg/min without bolus) every 2 weeks for 12 weeks. The primary endpoint was the effect on serum concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) throughout the treatment period in comparison with placebo. Secondary endpoints included evaluation of safety, clinical events and health-related quality of life (HRQoL). The area under the curve (AUC, pg.day/mL) of the levels of NT-proBNP over time for patients who received levosimendan was significantly lower than for the placebo group (344 × 10 [95% Confidence Interval (CI) 283 × 10 -404 × 10...
Journal of Cardiac Failure, 2007
Background: Levosimendan (LS) improves cardiac contractility without increasing myocardial oxygen demand. We administrated LS on a monthly intermittent 24-hour protocol and evaluated the clinical effect after 6 months in a randomized, open, prospective study. Methods and Results: Fifty patients (age 45e65 years) with LV systolic dysfunction and New York Heart Association (NYHA) III or IV were randomized in 2 groups. LS group (n 5 25) was compared with a control group (n 5 25) matched for sex, age, and NYHA class. LS was given monthly on a 24-hour intravenous protocol for 6 months. Patients were evaluated by specific activity questionnaire (SAQ) and echocardiography (ECHO) before and 3 to 5 days after last drug administration, whereas 24-hour Holter recording was performed before and during last drug administration. Patients in LS and control group had same baseline SAQ, ECHO, and Holter parameters. At the end of the study, a larger proportion of patients in the levosimendan group reported improvement in symptoms (dyspnea and fatigue) (65% versus 20% in controls, P ! .01). After 6 months, the LS group had a significant increase in LV ejection fraction versus controls (28 6 7 versus 21 6 4 %, P 5 .003), LV shortening fraction (15 6 3 versus 11 6 3 %, P 5 .006) and a decrease in mitral regurgitation (1.5 6 0.8 versus 2.7 6 0.6, P 5 .0001). There was no increase in supraventricular or ventricular beats or supraventricular tachycardia and VT episodes in LS group, compared with controls. Two patients from the LS group died in the 6-month follow-up period, compared with 8 patients in the control group (8% versus 32%, P ! .05). Conclusions: A 6-month intermittent LS treatment in patients with decompensated advanced heart failure improved symptoms and LV systolic function. (J Cardiac Fail 2007;13:556e559)